development of fda recommendations for deferral of donors based on risk of bse exposure
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Development of FDA Recommendations for deferral of donors based on risk of BSE exposureAlan E. Williams, Ph.D.Director, Division of Blood ApplicationsOffice of Blood Research and ReviewCBER, FDA
TSE Advisory CommitteeOctober 14, 2004
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Goals:Effective response to the spread of vCJD in Europe and the potential threat to blood safety
Optimal balance between vCJD risk reduction and blood supply preservation
Implementation plan that is sensitive to the dynamics of donor recruitment and blood resource sharing
Coherent and uniform national policy
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Empirical vCJ-D Risk ModelLikelihood of dietary exposureLength of incubation period (mean and range)Prevalence of asymptomatic carrier statePresence of vCJD agent in blood during incubation period/carrier stateSusceptibility of recipient population
VERY LIMITED DATA, THEREFORE AN EMPIRICAL MODEL IS NOT POSSIBLE
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Linear vCJD Risk Model Risk of exposure to BSE/vCJD is linear and related to the duration and likelihood of dietary exposure
Concept previously endorsed by TSEAC AssumptionsData regarding travel and residence in BSE-endemic country is a valid surrogate for:dietary exposure to BSE subsequent potential to transmit vCJD via blood
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1999 Blood Donor Travel SurveyProbability sample of accepted donors at twelve blood center sites - Winter, 1999.19,067 surveys - single page mailing with cover letter9,541 anonymous responses (~ 50%)UK (European) travel, sex, age, FT/Rpt, education Data requested by TSEAC and presented extensively at previous meetings.
Note: Donor survey estimates are reproducible, but are based upon self-report and have not been validated by other independent measures. Short survey - numerous data extrapolations.
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Any Blood Donor Travel/Residence: UK and any European Country with endemic BSE in 1999
Any UK Travel/residence 1980-1996 - 22.8%Range by blood center - 10.2 - 31.7%Higher travel with education, age, repeat status
Any European country with BSE in 1999 - 35.5%
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Possible Donor Exposures to BSE/vCJD Person-Days Exposure - Derived from total estimated cumulative time spent by donors in a defined geographic area
Donor loss - Estimated proportion of donors who spent time in a geographic area cut-off value
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Blood Supply ConcernsBlood Donor base~80% repeat donors (deferrals costly)Stressed by changing donor demographics and deferrals related to donor exposures and test results. AgingFewer large worksite collections
Elasticity of Supply3-5 % maximum donation loss experience (1986 anti-HBc; 2000 ear/finger stick + UK deferral)Limited supply during Summer and holidays (esp. 2002)
Public responds to appeals - long term impact uncertainCapability of monitoring supply impact
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UK BSE Exposure/Donor Loss Analysis (Based upon 252,804 total UK person-days exposure)
UK 6 month deferralUK p-d removed: 217,411/252,804 (86.0%)Residual total p-d: 35, 393 (14.0%)
Donor loss: 2.2% % p-d removed/1% donor loss: 39.1
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BSE Exposure/Donor Loss Analysis UK 3 months de novoUK p-d removed: 235,866/252,804 (93.3%)Residual total p-d: 16,938/252,804 (6.7%)
Donor loss: 3.4% % p-d removed/1% donor loss: 27.4
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BSE Exposure/Donor Loss Analysis UK 1 month de novo
UK p-d removed: 245,978/252,804 (97.3%)Residual total p-d: 6826/252,804 (2.7%)
Donor loss: 6.4% % p-d removed/1% donor loss: 15.2
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BSE Exposure/Donor Loss Analysis UK 1 month, given 3 month UK deferralAdditive UK p-d removed (based on total): 10,112/ 252,804 (4.0%)
Total p-d removed: 245,978/304,406 (97.3%)Residual total p-d: 6826/252,804 (2.7%)
Addl. donor loss: 3.0% % residual p-d removed /1% donor loss: 1.3
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Residual vCJD Risk (Theoretical) vs. Percent of Blood Supply Lost
Chart2
-14.90
-6.40.2
-3.42
-2.26.7
-1.515.6
20.8
% of Blood supply lost
Theoretical Residual vCJD risk remaining
(1 year)
(6 months)
(3 months)
(1 month)
(1 week)
% Blood supply lost
Residual vCJD risk remaining
Time spent in U.K. and/or Republic of Ireland (days)
Sheet1
22.61.3539109545days
?nNPercentLow CIHigh CI173656205
> 5 Years313185260.40.250.5253651825
19.71.2943053678> 3 Years306185260.70.550.9233651095
> 1 Year379885261.20.931.41365365
> 9 Months1211085261.31.061.55930.4166666667273.75
> 5 Months6217285262.01.732.34530.4166666667152.0833333333
> 1 Month24641885264.94.455.38130.416666666730.4166666667
> 11 Days5921010852611.811.1712.5511111
> 4 Days6691679852619.718.8520.55414
11.81.0735760455> 1 Day2471926852622.621.7123.49111
total19265505852664.6
logintvlintvldays%logdays%log%intvlpersonsintvl-midptperson-days
0.30102999572.0122.6022.61.3539109545> 5 Years314014.5124449.549.4
0.845098047.0419.70.602059991319.71.2943053678> 3 Years301459.543785.017.4
1.305530496920.21111.81.041392685211.81.0735760455> 1 Year37729.526991.510.7
1.957846633790.8304.91.48311161844.90.6904309535> 9 Months12318.93826.51.5
2.3271885894212.41522.02.18208162272.00.3047831186> 5 Months62212.413169.85.2
2.5036204716318.92741.32.43735412781.30.1106473568> 1 Month24690.822324.58.9
2.8630252962729.53651.22.56229286451.20.079181246> 11 Days59220.211963.34.8
3.16420409931459.510950.73.03941411920.7-0.1454154933> 4 Days6697.04683.01.9
3.60363146234014.518250.43.26126286880.4-0.4393836345> 1 Day2472.0494.00.2
6205251687.2100.0
YXY given XX given YX given YYXY given X
%expregressexpregressexpregress%expregress
22.6233.81954596623.9908203212829.771.0716.3
19.7716.26962818995.0478557908253.27619695442.0307.0
11.820.20833333338.75868747112.0502356303126.51037438533.0903.7
4.990.753.642681285554.568238753577.30917235344.01802.4
2.0212.41666666672.2166061722249.556582702852.76197959335.02701.9
1.3318.8751.748375354536.450252584838.61560010556.03651.6
1.2729.51.0782173545607.294622880629.65854794317.07301.1
0.71459.50.71909751472.004214946723.59759109568.018250.6
0.44014.50.39821558794690.104412969319.28832667749.062050.3
effective c/oCum% CJD Risk RemovedResidual CJD Risk RemainingCum% Loss of Blood Supply
intrvl
211000.0-20.8
7499.80.2-18.1
201198.02.0-11.0
913193.36.7-4.5-14.97
21215384.415.6-1.9-6.430
31927579.220.8-1.2-3.490
73036577.822.2-1.1-2.2180
1460109567.132.9-0.6-1.5365
4015182549.250.8-0.3-0.31825
2.00.3047831186
1.30.1106473568
1.20.079181246
0.7-0.1454154933
0.4-0.4393836345
Sheet1
0
0
0
0
0
0
0
0
0
days visited UK/ROI
percent of donors
Sheet2
22.589725545433.8195459662
19.692704668116.2696281899
11.84611775748.758687471
4.90265071553.6426812855
2.01735866762.2166061722
1.29017124091.748375354
Power Regression
Cumulative number of days in U.K. and/or Republic of Ireland
Percent of donors
Sheet3
22.5897255454
19.6927046681
11.8461177574
4.9026507155
2.0173586676
1.2901712409
1.2
0.7154585972
0.3635937133
0
0
0
0
0
0
0
(1 week)
(1 month)
(3 Months)
(6 Months)
(9 Months)
(1 year)
(2 years)
y = 50.699x-0.5841R2 = 0.9722
Y given X expregress
Days of travel to U.K. and/or Republic of Ireland
Percent of donors
Percent Loss of Donors by Amount of Time Spent in the U.K. and/or Republic of Ireland
0
0
0
0
0
0
0
0
0
Days of Travel to the U.K. and/or Republic of Ireland
Percent of donors
Amount of Time Spent in the U.K. and/or Republic of Ireland Given a Percentage of Donor Loss
0
0.2
2
6.7
15.6
20.8
22.2
32.9
50.8
effective c/o
Minimum interval cutoff (days)
Residual vCJD Risk Remaining
00
00
00
00
00
00
0
0
0
% of Blood supply lost
Theoretical Residual vCJD risk remaining
% Blood supply lost
Residual vCJD risk remaining
Time spent in U.K. and/or Republic of Ireland (days)
00
00
00
00
00
0
% of Blood supply lost
Theoretical Residual vCJD risk remaining
(1 year)
(6 months)
(3 months)
(1 month)
(1 week)
% Blood supply lost
Residual vCJD risk remaining
Time spent in U.K. and/or Republic of Ireland (days)
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Development of FDA Guidance issued November, 1999 June 2, 1999 TSEAC Guidance to Industry November 11, 1999Donor deferrals undertaken concurrent with a commitment to monitor the blood supply (estimated loss 2%)Donor deferrals recommended for:travel/residence in U.K. for >six months between 1980- 1996Receipt of bovine insulin sourced in the U.K. after 1980 Product retrieval recommended if donor later discovered to have vCJD
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Estimation of Potential BSE/vCJD Risk Remaining After November, 1999 Guidance Implementation
Chart2
32.3
13.6
11.2
42.9
Current R
Sheet1
UKEuropeEurobloodDoD Base
Total R794.33.613.6
Current R3213.611.242.9
TSEAC out05.4038.2
ARC out14.911.811.238.2
FDA out14.97.311.238.2
TSEAC res32.38.211.242.9
ARC res17.41.804.7
FDA res17.46.304.7
Sheet1
0
0
0
0
Current R
Current BSE/vCJD Exposure
Sheet2
Sheet3
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FDA/CDC Weighted Linear Risk Model for Estimating Possible Donor Exposure to BSE/vCJD Risk weighted by geographic exposure based on observations of UK beef imports, vCJD cases, and indigenous BSEUK = 1.0Epidemic focus, index countryFrance = 0.05 UK beef imports; obs. BSE, vCJDOther Europe (incl. Euroblood) = 0.015 Indigenous BSE, uncertain surveillance, reporting, food controls
(Note: Travel/residence in France calculated as ~ 0.7 UK based on overall travel prevalence)
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FDA/CDC Weighted Linear Risk Model for Estimating Possible Donor Exposure to BSE/vCJD
DoD active duty and dependents stationed on European bases = 0.35 (US bases supplied with ~ 35% UK beef)
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Development of Revised FDA Guidance issued January, 2002June 18-19, 2001 TSEACGuidance to Industry January, 2002 (deferrals)> 3 months residence/travel in U.K. 1980 - 1996 > 5 years residence/travel in Europe For donors of Source Plasma this criterion applies only to France (5-10% consumption of UK beef) > 6 months on certain US military bases in Europe between 1980-1990 or 1980-1996 (up to 35% UK beef consumed) Transfusion in the U.K. 1980 presentReceipt of bovine insulin sourced in the U.K. after 1980
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Estimated Further BSE/vCJD Risk Reduction Following Implementation of January, 2002 Revised Guidance
Current Risk reduced 72 % (Total Risk Reduced 91%)Option #3 (FDA)
Chart3
14.9
17.4
7.3
6.3
11.2
0
38.2
4.7
Sheet1
UKEuropeEurobloodDoD BaseUK outEur outDoD out
Total R794.33.613.6
Current R3213.611.242.9
TSEAC out05.4038.2
ARC out14.911.811.238.217.41.804.7
FDA out14.97.311.238.2
TSEAC res32.38.211.242.9
ARC res17.41.804.7
FDA res17.46.304.7
UK outUK leftEur outEur leftEbld outEbld leftDOD outDoD left
14.917.411.81.811.2039.24.7ARC
032.35.48.2011.238.24.7TSEAC
14.917.47.36.311.2038.24.7FDA
Sheet1
0
0
0
0
Current R
Current BSE/vCJD Exposure
Sheet2
0
0
0
0
0
0
0
0
Current BSE/vCJD Risk Removed by Option #2 (ARC)
Sheet3
0
0
0
0
0
0
0
0
Current BSE/vCJ-D Risk Removed by Option #1 (TSEAC)
0
0
0
0
0
0
0
0
Current BSE/vCJD Risk Removed by OPtion #3 (FDA Proposed)
MBD00164F82.xls
Chart1
78.6
4.3
3.6
13.6
Total R
Total BSE/vCJD Exposure
Sheet1
UKEuropeEurobloodDoD Base
Total R794.33.613.6
Current R3213.611.242.9
TSEAC out05.4038.2
ARC out14.911.811.238.2
FDA out14.97.311.238.2
TSEAC res32.38.211.242.9
ARC res17.41.804.7
FDA res17.46.304.7
Sheet1
0
0
0
0
Total R
Total BSE/vCJD Exposure
Sheet2
0
0
0
0
Current R
Current BSE/vCJD Exposure
Sheet3
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Revised FDA Guidance issued January, 2002 Advantages:Deferral tied to BSE observational data. Ratio of 3 mo. (UK) to 60 mos. (Europe) reflects worst case 5% European dietary estimate relative to UK . (3 mo. deferral for all of Europe in absence of weighting would add additional 7-8% donor loss)
Impact on NY area blood supply was severe, but was expected to be modulated by lesser impact elsewhere in US
Pilot provision allows flexibility for stricter policies
Some protection for human-human passage of vCJD
Recognizes food chain protections
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Revised FDA Guidance issued January, 2002 Disadvantages: At the time, transfusion-transmission of vCJD was theoretical
Donor screening questions are complex
Estimated 4-6% US donor loss exceeded past experience. Ability of rest of US to compensate for severe impact in NY area was untested.
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Observed Impact of 2002 Guidance on US Donor Base BSE/vCJD Deferrals phased in during May and October, 2002 Projected loss 5.0% nationwideActual loss not directly measurableMajor component of industry more restrictive
Disproportionate impacts of travel deferralsCoastal cities: 50% donor loss (e.g. NYC and SF) Rural US: 50% impact New York area Euroblood lost by pan-European deferralMilitary basesTSEAC requested supply monitoring and assessment
Seasonal and regional blood shortages persist
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Potential Future Challenges
Recent documentation of transfusion-transmission during vCJD asymptomatic incubation period
Deferral for UK transfusion in 2001 was precautionaryAdditional deferral of individuals with previous transfusion? (adaptation of vCJD agent)
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Chart4
5.41
5.35
5.56
5.53
5.41
5.05
4.65
4.05
4.05
3.98
Overall
Donation Year
Percentage
Percentage of Donations Given by TransfusedAllogeneic Donors, 1991-2000
Sheet1
1991199219931994199519961997199819992000
Overall5.415.355.565.535.415.054.654.054.053.98
Sheet1
0
0
0
0
0
0
0
0
0
0
Overall
Donation Year
Percentage of Allogeneic Donations
Percentage of Donations Given by Transfused Allogeneic Donors, 1991-2000
Sheet2
Sheet3
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Chart1
1.733.825.717.9810.9
1.593.65.497.8810.98
1.673.595.658.1311.41
1.563.435.538.0211.42
1.483.35.237.6911.31
1.333.044.77.1110.45
1.222.554.276.399.55
1.052.23.695.518.4
1.142.123.475.518.51
0.9723.395.328.39
=55
Donation Year
Percentage
Percentage of Donations Given by TransfusedAllogeneic Donors by Age, 1991-2000
Sheet1
1991199219931994199519961997199819992000
=5510.9010.9811.4111.4211.3110.459.558.408.518.39
Sheet1
00000
00000
00000
00000
00000
00000
00000
00000
00000
00000
=55
Donation Year
Percentage of Allogeneic Donations
Percentage of Donations Given by Transfused Donors Over Time
Sheet2
Sheet3
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Estimated Donor Loss Related to History of Transfusion in UK, France and Europe
Assumptions: 5% prevalence of transfusion in US donors overall (REDS data) >/= 5 yr travel/residence CONSERVATIVELY approximates lifetime transfusion exposurerate of tx among long term residents/travelers to Europe and UK = overall US donor prevalence prevalence of travel to France = 0.7 x travel to UK
Hx tx (UK - deferral already accomplished) 0.4 x 0.05 = 2/10,000
Hx Tx (any Europe, excl. UK) 0.7% x 0.05 = 3/10,000
Hx Tx (France) 0.4 x 0.7 x 0.05 = 1.4/10,0000
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Spread/Recognition of BSE/vCJD in New Geographic AreasNo exposure data available for donors beyond UK and European BSE Countries
Despite limitations, survey data provided a framework for risk:donor loss estimates
TSEAC may wish to consider new data collection efforts that will support future deliberations
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